Wang Shan, Tang Shanshan, Zhou Yuxin, An Qifei, Du Mengxing, Yang Xiujuan, Zou Peng, Tang Li, Yu Yufeng
Shanxi Key Laboratory of Functional Proteins, School of Basic Medical Sciences and Pharmacy, Shanxi Medical University, Taiyuan, China.
Department of Public Health Laboratory Sciences, School of Public Health, Shanxi Medical University, Taiyuan, China.
J Virol. 2025 Jun 23:e0040525. doi: 10.1128/jvi.00405-25.
Zika virus (ZIKV) infection of neuronal cells leads to endoplasmic reticulum (ER) stress, which is one of the key causes of neuronal damage. However, how ZIKV mediates ER stress has not been fully understood. Here, we observed that ZIKV infection of astrocytes elevated Sarco/endoplasmic reticulum Ca-ATPase (SERCA) expression, increased intracellular Ca concentration, and upregulated ER stress-related genes. SERCA2 was identified to regulate Ca homeostasis and ER stress during ZIKV infection through both knockdown and overexpression of SERCA2 in astrocytes. Furthermore, ZIKV NS2A interacted with SERCA2 and increased the expression of SERCA2, disrupted Ca homeostasis, and induced ER stress in astrocytes. After the knockdown of SERCA2 expression, Ca homeostasis and ER stress were significantly mitigated in astrocytes expressing NS2A. Additionally, pTMS1-2 and pTMS4-5 of NS2A interacted with SERCA2 and regulated Ca homeostasis and ER stress. ZIKV infection of the brains of BALB/c neonatal mice also elevated expression of SERCA2 and ER stress-related genes. Furthermore, SERCA2 expression facilitated ZIKV replication. These results suggested that ZIKV NS2A mediates ER stress through its interaction with SERCA2, providing new insights into the pathogenic mechanism of ZIKV and the development of anti-ZIKV therapies.
Zika virus (ZIKV) infection induces intracellular Ca imbalance and endoplasmic reticulum (ER) stress. However, the molecular mechanisms involved in it remain unknown. Here we reported, for the first time, that ZIKV infection increased the expression of Sarco/endoplasmic reticulum Ca-ATPase 2 (SERCA2), which plays a crucial role in regulating Ca homeostasis and ER stress. Furthermore, ZIKV NS2A was found to interact with SERCA2, contributing to the regulation of Ca homeostasis and ER stress during ZIKV infection. And ZIKV NS2A pTMS1-pTMS2 and pTMS4-pTMS5 were the specific sites that interacted with SERCA2. These findings elucidate that the interaction between NS2A and SERCA2 is responsible for the regulation of the upstream signaling pathway of ER stress mediated by ZIKV infection. Additionally, the expression of SERCA2 promoted ZIKV proliferation, indicating that SERCA2 may serve as a potential target for anti-ZIKV therapies.
寨卡病毒（ZIKV）感染神经元细胞会导致内质网（ER）应激，这是神经元损伤的关键原因之一。然而，ZIKV如何介导ER应激尚未完全明确。在此，我们观察到ZIKV感染星形胶质细胞会提高肌浆网/内质网Ca - ATP酶（SERCA）的表达，增加细胞内Ca浓度，并上调与ER应激相关的基因。通过在星形胶质细胞中敲低和过表达SERCA2，确定SERCA2在ZIKV感染期间调节Ca稳态和ER应激。此外，ZIKV NS2A与SERCA2相互作用，增加SERCA2的表达，破坏Ca稳态，并在星形胶质细胞中诱导ER应激。在敲低SERCA2表达后，表达NS2A的星形胶质细胞中的Ca稳态和ER应激得到显著缓解。此外，NS2A的pTMS1 - 2和pTMS4 - 5与SERCA2相互作用并调节Ca稳态和ER应激。对BALB/c新生小鼠脑内进行ZIKV感染也会提高SERCA2和与ER应激相关基因的表达。此外，SERCA2的表达促进了ZIKV的复制。这些结果表明，ZIKV NS2A通过与SERCA2相互作用介导ER应激，为ZIKV的致病机制及抗ZIKV疗法的开发提供了新见解。
寨卡病毒（ZIKV）感染会诱导细胞内Ca失衡和内质网（ER）应激。然而，其中涉及的分子机制仍不清楚。在此我们首次报道，ZIKV感染会增加肌浆网/内质网Ca - ATP酶2（SERCA2）的表达，其在调节Ca稳态和ER应激中起关键作用。此外，发现ZIKV NS2A与SERCA2相互作用，有助于在ZIKV感染期间调节Ca稳态和ER应激。并且ZIKV NS2A的pTMS1 - pTMS2和pTMS4 - pTMS5是与SERCA2相互作用的特定位点。这些发现阐明了NS2A与SERCA2之间的相互作用负责调节由ZIKV感染介导的ER应激上游信号通路。此外，SERCA2的表达促进了ZIKV的增殖，表明SERCA2可能作为抗ZIKV疗法的潜在靶点。
